rs2717477

Variant names:

• chr12-80378033-G-A
• rs2717477
• NM_001378609.3:c.7047G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-80378033-G-A
• chr12-80378033-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378609.3(OTOGL):​c.7047G>A​(p.Thr2349Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 1,577,228 control chromosomes in the GnomAD database, including 521,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2349T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.72 (40882 hom., cov: 31)
  • Exomes 𝑓: 0.82 (481090 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.90
• Publications: 19 publications found

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.061).
• BP6: Variant 12-80378033-G-A is Benign according to our data. Variant chr12-80378033-G-A is described in ClinVar as Benign. ClinVar VariationId is 226976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.7047G>A	p.Thr2349Thr	synonymous	Exon 59 of 59	NP_001365538.2
	OTOGL	NM_001378610.3		c.7047G>A	p.Thr2349Thr	synonymous	Exon 62 of 62	NP_001365539.2
	OTOGL	NM_173591.7		c.7047G>A	p.Thr2349Thr	synonymous	Exon 59 of 59	NP_775862.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.7047G>A	p.Thr2349Thr	synonymous	Exon 59 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.6912G>A	p.Thr2304Thr	synonymous	Exon 63 of 63	ENSP00000496036.1
	OTOGL	ENST00000298820.7	TSL:5	c.2241G>A	p.Thr747Thr	synonymous	Exon 18 of 18	ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.717 AC: 108874 AN: 151760 Hom.: 40880 Cov.: 31

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.783

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.792

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.758

GnomAD2 exomes AF: 0.769 AC: 152312 AN: 198162 AF XY: 0.783

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.619

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 0.765

Gnomad FIN exome AF: 0.793

Gnomad NFE exome AF: 0.838

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.818 AC: 1166610 AN: 1425350 Hom.: 481090 Cov.: 41 AF XY: 0.820 AC XY: 579030 AN XY: 705764

African (AFR) AF: 0.449 AC: 14790 AN: 32922

American (AMR) AF: 0.632 AC: 24869 AN: 39380

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 21265 AN: 25474

East Asian (EAS) AF: 0.772 AC: 29634 AN: 38400

South Asian (SAS) AF: 0.826 AC: 67593 AN: 81868

European-Finnish (FIN) AF: 0.799 AC: 41112 AN: 51462

Middle Eastern (MID) AF: 0.762 AC: 4360 AN: 5722

European-Non Finnish (NFE) AF: 0.839 AC: 915674 AN: 1091108

Other (OTH) AF: 0.802 AC: 47313 AN: 59014

GnomAD4 genome AF: 0.717 AC: 108904 AN: 151878 Hom.: 40882 Cov.: 31 AF XY: 0.718 AC XY: 53281 AN XY: 74236

African (AFR) AF: 0.468 AC: 19379 AN: 41366

American (AMR) AF: 0.703 AC: 10712 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2915 AN: 3470

East Asian (EAS) AF: 0.782 AC: 4022 AN: 5142

South Asian (SAS) AF: 0.819 AC: 3948 AN: 4820

European-Finnish (FIN) AF: 0.792 AC: 8377 AN: 10572

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57017 AN: 67950

Other (OTH) AF: 0.758 AC: 1601 AN: 2112

Alfa AF: 0.798 Hom.: 169643

Bravo AF: 0.695

Asia WGS AF: 0.782 AC: 2720 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.013
DANN	Benign	0.52
PhyloP100		-1.9
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2717477; hg19: chr12-80771813; COSMIC: COSV54014294;